The present invention is in the field of medicine, particularly in the treatment of states of insulin resistance that can result from disorders such as dibetes mellitus and its chronic complications such as retinopathy, polyneuropathy, nephropathy, angiopathy; gestational diabetes mellitus; impaired glucose tolerance; obesity; aging; atherosclerosis; syndrome X; cardiovascular disease; AIDS; cancer; wasting/cachecxia; sepsis; trauma associated with burns; malnutrition; lupus and other autoimmune diseases; endocrine diseases; hyperuricemia; hyperlipidemia; dyslipidemia; polycystic ovary syndrome; or complications arising from athletic activity.
Succinic acid is the physiologically occurring substrate of succinate dehydrogenase in mammals that play a role in cellular respiration and energy metabolism.
Insulin resistance is a condition in which the tissues of the body fail to respond normally to insulin. DeFronzo, R. A. J. Cardiomuscular Pharmacology 20 (Suppl. 11): S1-S16 (1992). The insulin resistance manifesting itself in pathologically elevated endogenous insulin and glucose levels and predisposes to the development of a cluster of abnormalities, including some degree of impaired glucose tolerance, an increase in plasma triglycerides and low density lipoprotein cholesterol (LDL) levels, a decrease in high-density lipoprotein cholesterol (HDL) levels, high blood pressure, hyperuricemia, a decrease in plasma fibrinolytic activity, an increase in cardiovascular disease and atherosclerosis. Reaven, G. M. Physiol-Rev. 75(3): 473-86 (1995). The decompensated insulin resistance is widely believed to be an underlying cause of non-insulin dependent diabetes mellitus.
A method of treating insulin resistance is known which comprises administration of insulin. Yki-Jarvinen, H. et al. N. Engl. J. Med. 327: 1426-1433 (1992). However, a basic disorder in the case of insulin resistance lies in the glucose assimilation by peripheral tissues of a mammal body. In this connection, it is important to treat the glucose assimilation not by the administration of insulin or by the pharmaceutical drug stimulating the excretion of insulin, but by the mechanisms independent thereof. Haering H. U., Mehnert H., Diabetologia 36: 176-182 (1993).
Free fatty acids induce insulin resistance in human in a dose dependent fashion. Boden G. Front. Biosci. 3, d169-175 (1998); Boden G., Diabetes 46(1): 3-10 (1997). Lowering of plasma free fatty acid levels is accordingly effective in the treatment of insulin resistance in a mammal.
Surprisingly, it has now been found that administration of an effective amount of succinic acid or salt thereof to insulin resistant mammals is effective therapy for treating of insulin resistance. Lowering of plasma free fatty acid levels accompanies a lowering of pathologically elevated insulin and glucose levels that reflects an improving in insulin sensitivity. More surprisingly, this biological effect is a long-term, and the best results are achieved in the after-treatment period.
This result is unexpected to Japanese Patent No. 61171417 describing that dicarboxylic acids including succinic acid are useful as antidiabetics showing promoting action on insulin secretion. More recently, MacDonald et al. demonstrated contrary to Japanese Patent No. 61171417 data that unesterified succinate, the compound of the present invention, did not stimulate insulin release in pancreatic islets but only esters of succinic acid are potent insulin secretagogues. MacDonald, M. J., Fahien, L. A. Diabetes 37(7): 997-999 (1988). Moreover, promotion of insulin secretion are useful in treating insulin dependent diabetic mammals with low or no insulin secretion, while insulin resistant mammals including non-insulin dependent diabetic mammals are needed in decreasing of elevated insulin levels rather than promotion of insulin secretion.
The present invention shows for the first time that succinic acid or salt thereof is useful for treating of insulin resistance in mammals, particularly in humans afflicted with non-insulin dependent diabetes mellitus.
It is an object of the present invention to provide the use of succinic acid or a pharmaceutically acceptable salt thereof for the manufacture of medicament or nutritional supplement useful for treating insulin resistance in a mammal.
It is an object of the present invention to provide a method of treating insulin resistance in a mammal, comprising administering to the mammal in need thereof of an effective amount of succinic acid or a pharmaceutically acceptable salt thereof. Orally, or parenterally, or topically, or rectally, as a nutritional supplement or medicament.
The present invention provides a method of treating insulin resistance in a mammal, which comprises administering to a mammal in need thereof an effective amount of succinic acid or a pharmaceutically acceptable salt thereof. Insulin resistance in the mammal can be associated with disorders such as diabetes mellitus and its chronic complications such as retinopathy, polyneuropathy, nephropathy, angiopathy; or gestational diabetes mellitus; or impaired glucose tolerance; or obesity; or aging; or atherosclerosis; or syndrome X; or cardiovascular disease; or AIDS; or cancer; or wasting/cachecxia; or sepsis; or trauma associated with burns; or malnutrition; or lupus and other autoimmune diseases; or endocrine diseases; or hyperuricemia; or hyperlipidemia; or dyslipidemia; or polycystic ovary syndrome; or complications arising from athletic activity. More particularly, the present invention provides the method of treating insulin resistance in a human afflicted with non-insulin dependent diabetes mellitus. Succinic acid has the chemical structure given below:
HOOCCH2CH2COOH
The pharmaceutically acceptable salt of the succinic acid is prepared by known methods from organic and inorganic bases. Such bases include, but are not limited to, nontoxic alkali metal and akaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide; ammonium hydroxide and nontoxic organic bases, such as triethylamine, butylamine, diethanolamine, triethanolamine and 2-ethyl-6-methyl-3-hydroxypyridine.
The succinic acid or a pharmaceutically acceptable salt thereof is preferably administered orally in the method of this invention. The succinic acid or a pharmaceutically acceptable salt thereof may also be administered by a variety of other routes such as parenterally, e.g. intravenously, subcutaneously, intramuscularly,; topically or rectally. Preferably, the succinic acid or pharmaceutically acceptable salt thereof is administered for a period of 1 day or longer; more preferably for a period of 3 to 7 days. The effective amount of succinic acid or a pharmaceutically acceptable salt thereof for use in the method of this invention is preferably from 0.1 milligram to 50 milligrams per day per kilogram of body weight of the mammalian subject, more preferably from 1 mg to 20 mg per day per kilogram of body weight of the mammalian subject.
Treating, as used herein, describes the managment and care of a mammal for the purpose of combating the disease, condition, or disorder and includes the administration of succinic acid or a pharmaceutically acceptable salt thereof to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition, or disorder. Treating of insulin resistance in a mammal includes increasing insulin sensitivity manifesting itself in a lowering of free fatty acid, insulin and glucose levels.
Also provided according to the present invention is the use of succinic acid or a pharmaceutically acceptable salt thereof for the manufacture of a medicament or nutritional supplement useful for treating insulin resistance in a mammal. Preferably, mammal is a human.
The medicaments or nutritional supplements of the invention are prepared by known procedures using well-known ingredients. In making the medicaments or nutritional supplements, the active ingredients will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, tablet, paper or other container. When the carrier serves as a diluent, it may be a solid, semisolid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. The nutritional supplements can be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules. The medicaments can be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, aerosoles, suppositories, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable carriers, diluents, and excipients include lactose, dextrose, sorbitol, mannitol, calcium phosphate, alginates, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate; stearic acid, and mineral oil. The medicaments or nutritional supplements can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
Preferably the medicament or nutritional supplement of the invention is in a dosage form and can be administrated orally, or parenterally, or topically, or rectally.
The medicament or nutritional supplement of the invention can be used advantageously in combination with antidiabetic drugs, particularly with insulin.
The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.